Genetic risk variants in African Americans with multiple sclerosis

Abstract

Objectives: To assess the association of established multiple sclerosis (MS) risk variants in 3,254 African Americans (1,162 cases and 2,092 controls).

Methods: Human leukocyte antigen (HLA)-DRB1, HLA-DQB1, and HLA-A alleles were typed by molecular techniques. Single nucleotide polymorphism (SNP) genotyping was conducted for 76 MS-associated SNPs and 52 ancestry informative marker SNPs selected throughout the genome. Self-declared ancestry was refined by principal component analysis of the ancestry informative marker SNPs. An ancestry-adjusted multivariate model was applied to assess genetic associations.

Results: The following major histocompatibility complex risk alleles were replicated: HLA-DRB1*15:01 (odds ratio [OR] = 2.02 [95% confidence interval: 1.54-2.63], p = 2.50e-07), HLA-DRB1*03:01 (OR = 1.58 [1.29-1.94], p = 1.11e-05), as well as HLA-DRB1*04:05 (OR = 2.35 [1.26-4.37], p = 0.007) and the African-specific risk allele of HLA-DRB1*15:03 (OR = 1.26 [1.05-1.51], p = 0.012). The protective association of HLA-A*02:01 was confirmed (OR = 0.72 [0.55-0.93], p = 0.013). None of the HLA-DQB1 alleles were associated with MS. Using a significance threshold of p < 0.01, outside the major histocompatibility complex region, 8 MS SNPs were also found to be associated with MS in African Americans.

Conclusion: MS genetic risk in African Americans only partially overlaps with that of Europeans and could explain the difference of MS prevalence between populations.

Figure 1. MS genetic burden scores in the 1000 Genomes Project population

Based on the 8 non-MHC MS SNPs for which the association with MS were replicated in African Americans (p < 0.01), aggregation of those SNPs was computed for individuals in the 1000 Genomes Project dataset, as previously described. Luhya in Webuye, Kenya, and Yoruba in Ibadan, Nigeria, are combined as “African”; Han Chinese in Beijing, China, Han Chinese South, and Japanese in Tokyo, Japan, are combined as “Asian”; Colombian in Medellin, Colombia, Mexican Ancestry in Los Angeles, CA, and Puerto Rican in Puerto Rico are combined as “Hispanic”; and Toscani in Italy, Iberian populations in Spain, Finnish from Finland, British from England and Scotland, and Northern and Western Europeans from Utah are combined as “European.” Additionally, genetic burden scores of our case-control dataset in AA and WA are included. A worldwide gradient of genetic burden scores was seen, matching MS prevalence in the world. Patients were more loaded than controls in both AA and WA. The p values at the top of the figure indicate the statistical significance of comparisons in groups next to each other (Wilcoxon rank sum test). The p value at the middle, bottom was calculated by Kruskal-Wallis test. Uncorrected p values are shown. AA = African Americans; ASW = African ancestry from southwest United States; K-W = Kruskal-Wallis test; MHC = major histocompatibility complex; MS = multiple sclerosis; SNP = single nucleotide polymorphism; WA = white Americans.